FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"AN IMPROVED PROCESS OF PREPARING RACEMATE OR EITHER ISOMER OF N, N-DIMETHYL-N-[-3-(2-NAPHTHYLOXY)-3-THIEN-2-YLPROPYL] AMINE AND ACID ADDITION SALT THEREOF"
Enaltec Labs Pvt Ltd. an Indian Company, having its Registered Office at 17th Floor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

AN IMPROVED PROCESS OF PREPARING RACEMATE OR EITHER ISOMER OF N, N-DIMETHYL-N-[-3-(2-NAPHTHYLOXY)-3-THIEN-2-YLPROPYL] AMINE AND ACID ADDITION SALT THEREOF
FIELD OF THE INVENTION:
The present invention relates to an improved process of preparing racemate or either isomer N, N-dimethyl-N-[3-(2-naphthyloxy)-3-thien-2-ylpropyl] amine and its acid addition salts thereof, an intermediate for the preparation of Duloxetine and its pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION:
Chemically Duloxetine is (+)-(S)-N-methyl-gamma-(l-naphthyloxy)-2-thiophene propylamine and is known from U.S.Patent No 5,023,269 and is represented by compound of structural formula I.

The proprietor name of Duloxetine hydrochloride is Cymbalta. Cymbalta is a serotonin and norepinephrine reuptake inhibitor and is indicated for the treatment of major depressive disorder; generalized anxiety disorder; diabetic peripheral neuropathic pain and fibromyalgia.

U.S.Patent No 5,023,269 described the process of preparing racemic duloxetine base compound of structural formula VI wherein α-[2-(Dimethylamino) ethyl] -2-thiophene methanol of structural formula II is condensed with 1-fluoronaphthalene compound of structural formula III in the presence of sodium hydride in dimethylacetamide solvent to get N, N-dimethyI-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine of structural formula IV, which is reacted with a phenyl chloroformate in toluene solvent to get a carbamate compound of structural formula V. The solution of carbamate compound of structural formula V in propylene glycol is reacted with 5N sodium hydroxide solution at 110°C for 75 minutes to get racemic duloxetine base compound of structural formula VI.

U.S.Patent No 5,362,886 described the process of preparing duloxetine compound of structural formula I, wherein (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine compound of structural formula VII is condensed with 1-fluoronaphthalene compound of structural formula III in the presence of sodium hydride and a potassium compound chosen from potassium benzoate or potassium acetate to get (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine

compound of structural formula VIII. The (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII is reacted with phenyl chloroformate in the presence of diisopropylethylamine in toluene solvent to get a carbamate compound of structural formula IX, which is reacted with sodium hydroxide in dimethyl sulphoxide solvent to get duloxetine compound of structural formula I.


U.S.Patent No. 7,538,232 described a process for preparing Duloxetine compound of structural formula I wherein (S)-α-[2-(methylamino) ethyl]-2-thiophenemethanol compound of structural formula X is condensed with 1 -fluoronaphthalene compound of structural formula III in the presence of potassium hydroxide in a mixture of toluene and dimethyl sulphoxide solvents. The U.S.Patent No. 7,538,232 also describes the process of preparing (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII by condensing (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine compound of structural formula VII with 1-fiuoronaphthalene compound of structural formula III in the presence of potassium hydroxide in an organic solvent selected from the group consisting of glyme, diglyme, triglyme or tetraglyme.

U.S.Patent No.7,645,890 described the process of preparing (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII by condensing (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine compound of structural formula VII with 1-fiuoronaphthalene compound of structural formula III in the presence of potassium hydroxide and 18-crown-6 in dimethyl sulphoxide solvent.
U.S.Patent No 6,541,688 described the process of preparing (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII by condensing (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine compound of structural formula VII with 1-fiuoronaphthalene compound of structural formula III

in the presence of alkali metal alkoxides in 1,3 -dimethyl -2 -imidazolidinone or N-methylpyrrolidinone at a temperature of from 0°C to 140°C.
U.S.Patent Publication No. 2007/0238883 described the process of preparing (S)-(+)-N,N-dimemyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII by condensing (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine compound of structural formula VII with l-fluoronaphthalene compound of structural formula III in the presence of base selected from the group consisting of alkali metal hydroxide, sodium metal alkoxides, lithium metal alkoxides in a polar aprotic solvent selected from the group consisting of dimethyl sulphoxide, dimethylformamide, dimethylacetamide, acetonitrile, sulfolane, nitromethane, propylene carbonate in the absence of a phase transfer catalyst.
U.S.Patent Publication No. 2010/0267968 described the process of preparing (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII by condensing (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine compound of structural formula VII with l-fluoronaphthalene compound of structural formula III in the presence of base selected from the group comprising of alkali metal hydroxide or alkaline earth metal hydroxide in the absence of an organic solvent.
The prior-art processes for preparing (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII involves the use of pyrophoric reagent like sodium hydride which is not safe for commercial scale production. The prior-art process for preparing (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII involves the use of high boiling solvents like dimethyl sulphoxide, glyme, diglyme, triglyme, tetraglyme, l,3-dimethyl-2-imidazolidinone, dimethylformamide, dimethylacetamide, acetonitrile. sulfolane, nitromethane, propylene carbonate or N-methylpyrrolidinone, which are very difficult to remove from the final duloxetine hydrochloride active pharmaceutical ingredient.
Accordingly there is a need in the art to develop an improved process for preparing racemate or either isomer of N, N-dimethyl-N-[-3-(2-naphthyloxy)-3-thien-2-ylpropyl] amine and its acid addition salt thereof.

SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide a process of preparing (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII comprises reacting (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine compound of structural formula VII with 1-fluoronaphthalene compound of structural formula III in a mixture of toluene and dimethyl sulphoxide solvents in the absence of phase transfer catalyst.
A second aspect of the present invention is to provide a process of preparing duloxetine base compound of structural formula I comprising the steps of:
a. reacting (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine
compound of structural formula VII with 1-fluoronaphthalene compound of
structural formula III in a mixture of toluene and dimethyl sulphoxide solvents
in the absence of phase transfer catalyst to get (S)-(+)-N,N-dimethyl-3-(l-
naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula
VIII,
b. reacting (S)-(+)-N,N-dimethyl-3-(l-naphthalenyIoxy)-3-(2-thienyl)
propanamine compound of structural formula VIII with phenyl chloroformate
to get a carbamate compound of structural formula IX and
c. converting carbamate compound of structural formula IX into duloxetine base
compound of structural formula I.
A third aspect of the present invention is to provide a process of preparing duloxetine hydrochloride comprising the steps of:
a. reacting (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine compound of structural formula VII with 1-fluoronaphthalene compound of
structural formula III in a mixture of toluene and dimethyl sulphoxide solvents
in the absence of phase transfer catalyst to get (S)-(+)-N,N-dimethyl-3-(l-
naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula
VIII,
b. reacting (SH+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII with phenyl chloroformate
to get a carbamate compound of structural formula IX,

c. converting carbamate compound of structural formula IX into duloxetine base
compound of structural formula I and
d. converting duloxetine base compound of structural formula I into duloxetine
hydrochloride.
A fourth aspect of the present invention is to provide a process for preparing N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine comprises reacting N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine with 1-fluoronaphthalene compound of structural formula III in a mixture of toluene and dimethyl sulphoxide solvents in the absence of phase transfer catalyst.
A fifth aspect of the present invention is to provide a process for preparing racemic duloxetine base by the steps comprising of:
a. reacting N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine with 1-
fluoronaphthalene compound of structural formula III in a mixture of toluene
and dimethyl sulphoxide solvents in the absence of phase transfer catalyst to
get N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine,
b. converting N,N-dimethyl-3-(l -naphthalenyloxy)-3-(2-thienyl) propanamine
into racemic duloxetine base,
c. converting racemic duloxetine base into duloxetine base compound of
structural formula I and
d. converting duloxetine base compound of structural formula I into duloxetine
hydrochloride.
DETAILED DESCRIPTION OF THE INVENTION:
(S)-(-)-N.N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine compound of structural formula VII may be prepared by methods known in the art such as those described in U.S. Patent Nos 5,362,886 and PCT Publication no. 2010/079404, which are incorporated herein by reference only.

The reaction of (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine compound of structural formula VII with 1-fluoronaphthalene compound of structural formula III in a mixture of toluene and dimethyl sulphoxide solvents in the absence of phase transfer catalyst may be carried out at a temperature in the range of 80°C to 125°C for a period of 2 hours to 6 hours to get (S)-(+)-N,N-dirnethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII.
The reaction of (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine compound of structural formula VII with 1-fluoronaphthalene compound of structural formula III in a mixture of toluene and dimethyl sulphoxide solvents may be carried out in the presence of potassium hydroxide.
The reaction of (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine compound of structural formula VII with 1 -fluoronaphthalene compound of structural formula III in a mixture of toluene and dimethyl sulphoxide solvents may be carried out in the presence of alkali metal iodide.
The example of alkali metal iodide may include sodium iodide.
The phase transfer catalyst referred in step a may include tetrabutyl ammonium bromide, or 18-crown-6.
The ratio of dimethyl sulphoxide and toluene may be in the range of 90:10 to 50:50 % volume/volume.
The (S)-(+)-N,N-dimethyI-3-(1-naphthatenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII may be isolated by quenching the reaction mixture by water, followed by the adjustment of pH of reaction mixture up to 4.8 by dilute hydrochloric acid. The aqueous layer may be separated and washed by n-Heptane and then the aqueous layer may be extracted with an ether solvent at pH 12.5.
The pH of aqueous layer may be adjusted with a 50% aqueous sodium hydroxide solution.

The examples of ether solvents may include diethyl ether, diisopropyl ether or methyl tertiary butyl ether.
The reaction of (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine compound of structural formula VII with 1-fiuoronaphthalene compound of structural formula III in a mixture of toluene and dimethyl sulphoxide solvents produces optically pure (S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII and partial racemization of (S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII is not observed.
Optically pure (S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII described herein refers to a compound having more than 99.5% enantiomeric purity.
Optically pure (S)-(+)-N, N-dimethy]-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII described herein refers to a compound having less than 0.25% weight / weight of (R)-(-)-N, N-dimethyl-3-(l-naphthaleny1oxy) -3 -(2 -thieny 1) propanamine.
The (S)-(+)-N, N-dimethyl-3-(l-naphthaIenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII may be isolated as an oxalate salt in a mixture of an alcohol and an alkyl acetate solvent.
Examples of alcohol solvent may include methanol, ethanol, propanol, n-butanol, isobutanol, or mixture(s) thereof.
Examples of alkyl acetate solvent may include methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixture(s) thereof.
The oxalate salt of (S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII may be isolated by the steps of filtration, centrifugation, washing, drying or the combination thereof.

The oxalate salt of (S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII may be dried at a temperature in the range of 45°C to 60°C under reduced pressure for a period of 4 hours to 18 hours.
The oxalate salt of (S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII may be converted into (S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine free base by reacting oxalate salt of (S)-(+)-N, N-dimethy]-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII with an sodium hydroxide in toluene solvent.
The solution of (S)-(+)-N, N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII in toluene may be reacted with phenyl chloroformate in the presence of diisopropylethylamine to get a carbamate compound of structural formula IX.
The reaction of (S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII with phenyl chloroformate in the presence of diisopropylethylamine in toluene may be carried out at a temperature in the range of 40°C to 75°C for a period of 2 hours to 6 hours to get a carbamate compound of structural formula IX.
The carbamate compound of structural formula IX may be isolated by quenching the reaction mixture with 1% sodium bicarbonate solution at a temperature in the range of 40°C to 55°C followed by washing the organic layer with water and saturated sodium chloride solution.
The solution of carbamate compound of structural formula IX in toluene may be concentrated under reduced pressure to get a residue.
The residue of carbamate compound of structural formula IX may be dissolved in dimethyl sulphoxide solvent.

The solution of carbamate compound of structural formula IX in dimethyl sulphoxide solvent may be treated with sodium hydroxide solution at a temperature in the range of 40°C to 60°C for a period of 12 hours to 28 hours to get a duloxetine base compound of structural formula I
The duloxetine base compound of structural formula I may be isolated by quenching the reaction mixture with water, followed by the adjustment of pH up to 5.0 with acetic acid.
The reaction mixture may be further diluted with n-Heptane and then aqueous layer may be isolated.
The aqueous layer may be extracted with an alkyl acetate solvent at pH in the range of 10.2 to 10.7.
The pH of aqueous layer may be adjusted with an aqueous sodium hydroxide solution.
The duloxetine base compound of structural formula I may be converted into duloxetine hydrochloride by reacting alkyl acetate solution of duloxetine base with a hydrochloric acid solution at a temperature in the range of 0°C to 5°C for a period of 1 hour to 4 hours.
The duloxetine hydrochloride may be isolated by the steps of filtration, centrifugation, washing, drying or the combination thereof.
The duloxetine hydrochloride may be washed with ethyl acetate solvent.
The duloxetine hydrochloride may be dried at a temperature in the range of 40°C to 65°C under reduced pressure for a period of 4 hours to 24 hours.
The duloxetine hydrochloride obtained by following the present invention may be crystalline or amorphous in nature.

The racemic duloxetine base may be obtained by following the same chemistry as being followed to prepare duloxetine base compound of structural formula I.
The racemic duloxetine base may be converted into duloxetine base compound of structural formula I by resolving racemic duloxetine base with dibenzoyl-L-tartaric acid in an aromatic hydrocarbon solvent.
The examples of aromatic hydrocarbon solvent may include toluene, xylene, cresol or mixture(s) thereof.
EXAMPLE:
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example-1: Preparation of N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine Oxalate
A mixture of fluoronaphthalene (23.66gm) and potassium iodide (21.5gm) in dimethyl sulphoxide (90ml) and toluene (10ml) was heated to 120°C and then 3-(dimethylamino)-l-(2-thienyl)-l-propanoI (20gm) and potassium hydroxide (7.25gm) were charged into the reaction mixture at 120°C and then resulting reaction mixture was agitated for 6 hours at 120°C. The reaction mixture was quenched with water (300ml), pH was adjusted up to 4.8 with dilute hydrochloric acid, aqueous layer was washed with n-heptane (3x 100ml) and then the pH of aqueous layer was again adjusted to 12.5 with aqueous sodium hydroxide solution. The aqueous solution was extracted with methyl tertiary butyl ether (3x100ml). The solution of N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine in methyl tertiary butyl ether was treated with an oxalic acid (9.7 lgm) solution in methanol (50ml) and ethyl acetate (100ml) and resulting solution was stirred for 15 minutes at 80-85°C. The resulting reaction mixture was concentrated under reduced pressure to get a residue compound, which was dissolved in ethyl acetate (200ml) and stirred for 1 hour at 50-55°C. The

resulting reaction mixture was cooled to 0°C and again stirred for 2 hours at 0-5°C
and then resulting solids were filtered, washed with ethyl acetate (75ml) and dried
under reduced pressure at 50-55°C to get title compound.
Yield: 40 gm
Purity: 99.86% (By HPLC)
Example-2: Preparation of (S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine Oxalate
A mixture of fluoronaphthalene (24gm) and potassium iodide (20gm) in dimethyl sulphoxide (90ml) and toluene (10ml) was heated to 110°C. The (S)-(-)-3-(dimethylamino)-l-(2-thienyl)-l-propanol (20gm) and potassium hydroxide (7.5gm) were charged into the reaction mixture at 110°C and then resulting reaction mixture was agitated for 6 hours at 120°C. The resulting reaction mixture was quenched with water (300ml), pH was adjusted up to 4.8 with dilute hydrochloric acid, aqueous layer was washed with n-heptane (3x100ml) and then the pH of aqueous layer was again adjusted to 12.5 with aqueous sodium hydroxide solution. The aqueous solution was extracted with methyl tertiary butyl ether (3x100ml). The solution of (S)-(-)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyI) propanamine in methyl tertiary butyl ether was treated with an oxalic acid (9.7lgm) solution in methanol (50ml) and ethyl acetate (100ml) and resulting solution was stirred for 15 minutes at 80-85°C. The resulting reaction mixture was concentrated under reduced pressure to get a residue compound, which was dissolved in ethyl acetate (250ml) and stirred for 2 hours at 50-55°C. The resulting reaction mixture was cooled to 0°C and again stirred for 1.5 hours at 0-5°C and then resulting solids were filtered, washed with ethyl acetate (100ml) and dried under reduced pressure at 50-55°C to get title compound. Yield: 37 gm Purity: 99.76% (By HPLC)
Example-3: Preparation of Duloxetine Hydrochloride
A solution of (S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine oxalate (25gm) in water (175ml) and toluene (150ml) was added 2N aqueous sodium hydroxide solution (80ml) and then resulting solution was stirred for 2 hours at 25-

30°C. The organic layer was separated, washed with water (2x100ml), dried over anhydrous sodium sulfate (25 gm) and concentrated under reduced pressure to get a residue. The solution of resulting residue in toluene (75ml) was reacted with phenyl chloroformate (20gm) in the presence of diisopropylethylamine (20gm) at 50-55°C for 2 hours. The resulting reaction mixture was quenched with 1 % sodium bicarbonate solution (200ml) and the organic layer was separated, washed with water (2x100ml), saturated sodium chloride solution (2x100ml), dried over anhydrous sodium sulfate (50gm) and concentrated under reduced pressure at 55°C to get a residue compound. The solution of residue in dimethyl sulphoxide (300ml) was treated with aqueous sodium hydroxide solution (12.5gm dissolved in 100ml water) at 48-52°C for 18 hours. The resulting reaction mixture was quenched with water (250ml), pH was adjusted to 5.0 with acetic acid and aqueous layer was washed with n-heptane (2x100ml). The pH of aqueous layer was adjusted to 10.7 with aqueous sodium hydroxide solution, and then it was extracted with ethyl acetate (125ml). The ethyl acetate layer was charcoalized with activated carbon (2.5gm) and then hydrochloric acid (2ml, 33% aqueous solution) was added and then resulting reaction mixture was stirred for 2 hours at 0-5°C and then resulting solids were filtered, washed with ethyl acetate (25ml) and dried under at 50°C under reduced pressure. Yield: 17.5gm Purity: 99.97% (By HPLC)

WE CLAIM:
1. A process of preparing (S)-(+)-N,N-dimethy]-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII comprises reacting (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine compound 0f structural formula VII with 1-fluoronaphthalene compound of structural formula III in a mixture of toluene and dimethyl sulphoxide solvents in the absence of phase transfer catalyst.

2. A process of preparing duloxetine base compound of structural formula I comprising the steps of:
a. reacting (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine
compound of structural formula VII with 1 -fluoronapthlene compound of structural formula III in a mixture of toluene and dimethyl sulphoxide solvents in the absence of phase transfer catalyst to get (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII,


b. reacting (S)-(+)-N,N-dimethyl-3-( 1 -naphthalenyloxy)-3-(2-thienyl)
propanamine compound of structural formula VIII with phenyl chloroformate to get a carbamate compound of structural formula DC and

c. converting carbamate compound of structural formula IX into duloxetine base compound of structural formula I.

3. A process of preparing duloxetine hydrochloride comprising the steps of:

a. reacting (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine
compound of structural formula VII with 1-fluoronaphthalene compound of structural formula III in a mixture of toluene and dimethyl sulphoxide solvents in the absence of phase transfer catalyst to get (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine compound of structural formula VIII,

b. reacting (S)-(+)-N,N-dimethyl-3-( 1 -naphthalenyloxy)-3-(2-thienyl)
propanamine compound of structural formula VIII with phenyl chloroformate to get a carbamate compound of structural formula IX,

c. converting carbamate compound of structural formula IX into duloxetine base compound of structural formula I and


d. converting duloxetine base compound of structural formula I into duloxetine hydrochloride.
4. A process for preparing N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine comprises reacting N, N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine with 1-fluoronaphthalene in a mixture of toluene and dimethyl sulphoxide solvents in the absence of phase transfer catalyst.
5. A process for preparing racemic duloxetine base by the steps comprising of:
a. reacting N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine with 1-
fluoronaphthalene in a mixture of toluene and dimethyl sulphoxide solvents in
the absence of phase transfer catalyst to get N,N-dimethyl-3-(l -
naphthalenyloxy)-3-(2-thienyl) propanamine,
b. converting N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine
into racemic duloxetine base,
c. converting racemic duloxetine base into duloxetine base compound of
structural formula I and
d. converting duloxetine base compound of structural formula I into duloxetine
hydrochloride.
6. The process according to claim nos 1, 2, 3, 4 or 5, wherein the ratio of dimethyl sulphoxide and toluene is in the range of 90:10 to 50:50 % volume/volume.
7. The process according to claim nos 1, 2, 3, 4 or 5, wherein the phase transfer catalyst is tetrabutyl ammonium bromide, or 18-crown-6.

8. The process according to claim nos 1, 2 or 3 wherein the reaction of (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine compound of structural formula VII with 1 -fiuoronaphthalene compound of structural formula III is carried out in the presence of potassium hydroxide and sodium iodide.
9. The process according to claim no 4 or 5 wherein the reaction of N, N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine with 1-fluoronaphthalene is carried out in the presence of potassium hydroxide and sodium iodide.
10. A process for the preparation of duloxetine hydrochloride as herein described in
specification and examples.